FOXO3a mediates signaling crosstalk that coordinates ubiquitin and atrogin-1/MAFbx expression during glucocorticoid-induced skeletal muscle atrophy
| Autor: | Tiffany K. Roberts-Wilson, S. Russ Price, Sakae Ohkawa, Bin Zheng, Haiyan Li |
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| Rok vydání: | 2010 |
| Předmět: |
MAPK/ERK pathway
Muscle Fibers Skeletal Muscle Proteins Biochemistry Research Communications Ubiquitin Genetics medicine Animals Molecular Biology Protein kinase B Glucocorticoids PI3K/AKT/mTOR pathway SKP Cullin F-Box Protein Ligases biology Forkhead Box Protein O3 Forkhead Transcription Factors Receptor Cross-Talk Muscle atrophy Ubiquitin ligase Rats Muscular Atrophy Gene Expression Regulation biology.protein Cancer research Phosphorylation medicine.symptom Signal transduction Biotechnology Signal Transduction |
| Zdroj: | FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 24(8) |
| ISSN: | 1530-6860 |
| Popis: | Muscle atrophy is a consequence of chronic diseases (e.g., diabetes) and glucocorticoid-induced insulin resistance that results from enhanced activity of the ubiquitin-proteasome pathway. The PI3K/Akt pathway inhibits the FOXO-mediated transcription of the muscle-specific E3 ligase atrogin-1/MAFbx (AT-1), whereas the MEK/ERK pathway increases Sp1 activity and ubiquitin (UbC) expression. The observations raise a question about how the transcription of these atrogenes is synchronized in atrophic muscle. We tested a signaling model in which FOXO3a mediates crosstalk between the PI3K/Akt and MEK/ERK pathways to coordinate AT-1 and UbC expression. In rat L6 myotubes, dexamethasone (≥24 h) reduced insulin receptor substrate (IRS)-1 protein and PI3K/Akt signaling and increased AT-1 mRNA. IRS-2 protein, MEK/ERK signaling, Sp1 phosphorylation, and UbC transcription were simultaneously increased. Knockdown of IRS-1 using small interfering RNA or adenovirus-mediated expression of constitutively activated FOXO3a increased IRS-2 protein, MEK/ERK signaling, and UbC expression. Changes in PI3K/Akt and MEK/ERK signaling were recapitulated in rat muscles undergoing atrophy due to streptozotocin-induced insulin deficiency and concurrently elevated glucocorticoid production. IRS-1 and Akt phosphorylation were decreased, whereas MEK/ERK signaling and expression of IRS-2, UbC and AT-1 were increased. We conclude that FOXO3a mediates a reciprocal communication between the IRS-1/PI3K/Akt and IRS-2/MEK/ERK pathways that coordinates AT-1 and ubiquitin expression during muscle atrophy.—Zheng, B., Ohkawa, S., Li, H., Roberts-Wilson, T.-K., Price, S. R. FOXO3a mediates signaling crosstalk that coordinates ubiquitin and atrogin-1/MAFbx expression during glucocorticoid-induced skeletal muscle atrophy. |
| Databáze: | OpenAIRE |
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